EP1165049B2 - Agglomerats obtenus par cristallisation - Google Patents

Agglomerats obtenus par cristallisation Download PDF

Info

Publication number
EP1165049B2
EP1165049B2 EP00917035A EP00917035A EP1165049B2 EP 1165049 B2 EP1165049 B2 EP 1165049B2 EP 00917035 A EP00917035 A EP 00917035A EP 00917035 A EP00917035 A EP 00917035A EP 1165049 B2 EP1165049 B2 EP 1165049B2
Authority
EP
European Patent Office
Prior art keywords
agglomerates
beta
potassium clavulanate
solvent
lactam
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP00917035A
Other languages
German (de)
English (en)
Other versions
EP1165049A2 (fr
EP1165049B1 (fr
Inventor
Johannes Booij
Ageeth Geertruida Lefferts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=8240058&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1165049(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Priority to DE60008508T priority Critical patent/DE60008508T9/de
Priority to EP00917035A priority patent/EP1165049B2/fr
Priority to SI200030366T priority patent/SI1165049T2/sl
Publication of EP1165049A2 publication Critical patent/EP1165049A2/fr
Application granted granted Critical
Publication of EP1165049B1 publication Critical patent/EP1165049B1/fr
Publication of EP1165049B2 publication Critical patent/EP1165049B2/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the present invention describes agglomerates of ß-lactam compounds in crystalline form and a process to prepare the same.
  • ⁇ -Lactam antibiotics constitute the most important group of antibiotic compounds, with a long history of clinical use. Among this group, the prominent ones are the penicillins and cephalosporins.
  • ⁇ -lactam antibiotics used are prepared by semisynthetic methods. These ⁇ -lactam antibiotics are obtained by modifying a ⁇ -lactam product obtained by fermentation by one or more reactions.
  • Clavulanic acid and its alkaline metal salts and esters act as ⁇ -lactamase inhibitors, able to enhance the effectiveness of penicillins and cephalosporins.
  • Clavulanic acid has been applied therefore in pharmaceutical compositions to prevent inactivation of ⁇ -lactam antibiotics.
  • the antibacterial activity profile of amoxicillin is enhanced by the use of potassium clavulanate as ⁇ -lactamase inhibitor.
  • a combination preparation of amoxicillin trihydrate with potassium clavulanate (Augmentin® ) is well known.
  • antibiotic compounds in powder form are not suitable for formulation purposes, because generally these powders perform badly as far as flowability is concerned which causes problems in the manufacturing of final dosage forms, such as tablets. Accurate dosing of the several ingredients is needed to ensure constant end product quality. in case of poor flowabilities, such accurate dosing is difficult to guarantee. Also, the needle shaped crystals, such as of potassium clavulanate, often show a low bulk density. Thus, the contribution of such crystals to the overall volume of the final dosage form is relatively high.
  • potassium clavulanate with excipients such as microcrystalline cellulose like Avicel® or silica like Syloid® or Aerosil®
  • granules of composition for example potassium clavulanate with other active ingredients like amoxicillin trihydrate
  • potassium clavulanate with other active ingredients like amoxicillin trihydrate are made before producing the final formulation.
  • Several processes are known to form such granules.
  • potassium clavulanate can be mixed with, for instance, amoxicillin and a binding agent after which the mixture is moistened by a solvent, granulated and bounded. Before tabletting the granules with excipients, the granulates might be sieved.
  • This wet granulation process is economically unattractive, as it uses solvents which must be recovered and/or recycled. It is labour intensive, expensive and time consuming due to the large number of processing steps such as mixing, granulating, sieving, drying etc. Moreover, in case of unstable ⁇ -lactam compounds such as potassium clavulanate, wet granulation is problematic due to the use of a solvent and high temperature during the drying step of the process.
  • Another method to granulate poor flowing powders is dry granulation.
  • the slugging process can be mentioned as described in International patent applications WO 9116893 and WO 9219227 .
  • tablets of the poor flowing material with excipients are made and subsequently broken again and sieved to produce granules.
  • Another example of dry granulation is the compaction process as described in International patent application WO 9528927 .
  • a process has been mentioned wherein compacted granules of a ⁇ -lactam antibiotic, for example amoxicillin, and a mixture of an active ⁇ -lactam antibiotic and a secondary pharmaceutically active agent, for example potassium clavulanate with excipients are made using roller compacting.
  • roller compacted flakes are milled, resulting in granules which can be mixed with excipients to press the final tablets.
  • An advantage compared to the wet granulation is the absence of solvents.
  • the dry granulation is relatively time consuming due to a large number of processing steps.
  • a quality risk exists due to locally high temperatures in the process, e.g. due to abrasion.
  • the material is hygroscopic, such as potassium clavulanate
  • another disadvantage is the handling of the dried crystals before and during the granulation process. During this handling, the product might attract water leading to unwanted degradation reactions.
  • a major disadvantage of roller compacted products is the relatively large amount of fines which should be removed using sieving techniques to improve the flowability of such products.
  • Granules of the active ingredient in the presence of excipients are produced by the process mentioned above. It would be advantageous to have the possibility to produce granules of the pure active ingredient. In that case, the production process can be more flexible and possibly overall less excipients are necessary. Also the production of final dosage forms will be more flexible. In case of hygroscopic substances such as potassium clavulanate, however, it will be difficult to granulate using one of the above processes without the presence of excipients like microcrystalline cellulose or silica, as the latter are known to protect the hygroscopic potassium clavulanate by removing the free water from it and, thus, keeping the water activity of such compositions low.
  • Another method to improve the flowability of needle shaped crystals, especially in the case of potassium clavulanate, is to agglomerate them during crystallisation to the so-called rosette form as described in European patent EP 277008 B1 .
  • a plurality of needle crystals radiate out from a common nucleation point.
  • the rosettes show an increased flowability compared to the needles.
  • a large disadvantage of these types of granules is the inclusion of impurities, leading to a decreased chemical quality of the product.
  • the included impurities probably increase the degradation rate of the ⁇ -lactam compound, thus resulting in an even worse chemical quality during storage.
  • the object of the invention is to provide a valuable form of a ß-lactam antibiotic compound and a process to prepare such a compound that overcomes most of the above mentioned disadvantages.
  • novel agglomerates in crystalline form of ⁇ -lactam antibiotics in a liquid phase are produced through a crystallisation process when a solution of at least one ⁇ -lactam compound in a solvent or in a mixture of solvents under stirring is mixed together with one or more anti-solvents.
  • one or both solutions contain water.
  • the present invention provides agglomerates in crystalline form comprising one or more ⁇ -lactam compounds having at least one ⁇ -lactam compound of a high water affinity, and optionally contain one or more excipients with the proviso that the agglomerates are obtainable by a process wherein agglomerates of controlled average particle size are produced in a liquid phase by applying stirring devices and a nozzle-sprayer.
  • said agglomerates comprise clavulanic acid or a pharmaceutically acceptable salt thereof like potassium clavulanate.
  • the agglomerates comprising potassium clavulanate may contain amoxicillin as the active ⁇ -lactam antibiotic compound.
  • the term agglomerate refers to clustering of the crystals of a compound.
  • the excipients are microcrystalline cellulose, preferably Avicel® , or silica, preferably Syloid® or Aerosil® .
  • the said agglomerates can also be of sterile form.
  • the new agglomerates are of an average particle size between about 1 ⁇ m and 1500 ⁇ m, preferably between about 500 ⁇ m and 1500 ⁇ m, more preferably between 800 ⁇ m and 1200 ⁇ m, or between 1 ⁇ m and 300 ⁇ m, preferably between 1 ⁇ m and 200 ⁇ m.
  • the agglomerates of the present invention are substantially free from non-agglomerated ⁇ -lactam crystals, for instance, non-agglomerated crystals having a weight percentage between 0-10%.
  • the agglomerates are produced in a liquid phase medium, which process involves mixing together a solution or suspension of at least one ß-lactam compound corresponding to the ⁇ -lactam compound to be prepared in agglomerate form in a solvent or in a mixture of solvents under stirring with one or more anti-solvents, whereby at least one of both solvents and cosolvent contains water.
  • the overall weight ratio of the solution containing the ⁇ -lactam compound to anti-solvent is about 0.05 to 10%.
  • the solvent is for instance water or ethanol and the anti-solvent a ketone, like acetone, methylethylketone, methylisobutylketone or an ester, like methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate or an alcohol, like 1-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or a mixture of these solvents.
  • the pH of the solution of the ⁇ -lactam compound may be adjusted to neutral.
  • the solvent is water or ethanol and the anti-solvent is acetone or ethyl acetate with some water present in at least the solvent or the anti-solvent. It is possible also to add other ingredients in one of the streams (solvent, anti-solvent or mixture thereof), either suspended or dissolved.
  • one or more stirring devices are used to crystallise, agglomerate and deagglomerate, or to crystallise and agglomerate, or to crystallise and deagglomerate the ß-lactam compound and optionally classification and blending with excipients and/or another ß-lactam compound in a batch or continuous operation in one or more reaction vessels or in one integrated step.
  • the operation is performed by applying stirring devices in one or more vessels, in-line mixers or a combination thereof.
  • agglomerates with various particle sizes can be prepared by using a nozzle-sprayer for the ß-lactam containing solution.
  • the agglomerates of various particle sizes are regulated by further using a combination and permutation of different stirring devices and their speed, the type and amount of the solvents used and the way of mixing of the solvents.
  • Agglomerates of potassium clavulanate of the present invention show a good level of stability and hygroscopicity.
  • agglomerates prepared according to the present invention, with one or more pharmaceutical acceptable excipients are suitable for pharmaceutical formulations.
  • compositions comprising amoxicillin, preferably amoxicillin trihydrate and the crystalline agglomerates of potassium clavulanate of the present invention and optionally one or more pharmaceutically acceptable inert excipients form another aspect of the present invention.
  • a pharmaceutical formulation comprising crystalline agglomerates of amoxicillin trihydrate and potassium clavulanate and one or more pharmaceutically acceptable inert excipients can be made.
  • the agglomerates are suitable to prepare oral dosage forms such as tablets, capsules, syrups or sachets, dry instant or ready to use in multiple or single dose form.
  • the oral dosage form comprising agglomerates or granules of amoxicillin with or without one or more excipients can also contain a ⁇ -lactamase inhibitor such as potassium clavulanate, preferably in the agglomerated form. Said agglomerates can also be used in Dose Sipping devices.
  • the present invention provides economically interesting agglomerates in crystalline form of a ⁇ -lactam compound.
  • the ⁇ -lactam compounds are for instance clavulanic acid but one can also think of amoxicillin or ampicillin.
  • the compound can be in the salt form, such as amine or alkaline metal salt.
  • agglomerates of potassium clavulanate are produced.
  • the agglomerates of said invention have an average particle size between about 1 ⁇ m and 1500 ⁇ m, preferably between about 500 ⁇ m and 1 500 ⁇ m, more preferably between 800 ⁇ m and 1200 ⁇ m, or between 1 ⁇ m and 300 ⁇ m, preferably between 1 ⁇ m and 200 ⁇ m.
  • said agglomerates are preferably substantially free from non-agglomerated ⁇ -lactam crystals, as for instance in the needle form.
  • substantially free from non-agglomerated crystals is meant that the agglomerates have a weight percentage between 0-10% of non-agglomerates.
  • a process for the preparation of the agglomerates, wherein one or more ⁇ -lactam compounds with or without excipients are used, consists of a crystallisation procedure to build up agglomerates.
  • the process comprises mixing together a solution or suspension of one or more ⁇ -lactam compounds corresponding to the agglomerates to be produced in a solvent or in a mixture of solvents with one or more anti-solvents under stirring.
  • the combination of solvent and anti-solvent can result in an emulsion.
  • an amount of water should be present, for instance in an amount of 0.05 to 10%.
  • the agglomerates are filtered off, washed and dried.
  • a anti-solvent is defined as a liquid in which the ⁇ -lactam compound does not dissolve or dissolves only poorly.
  • the ⁇ -lactam compound for instance potassium clavulanate
  • an appropriate solvent or a mixture of (partly) miscible solvents such as water, alcohols, like ethanol, methanol, 1-propanol, 2-butanol, 2-methyl-propanol, ketones, like acetone, methylethylketone, methylisobutylketone, or an ester, like methyl acetate, ethyl acetate, butyl acetate, with at least a small amount of water present.
  • miscible solvents such as water, alcohols, like ethanol, methanol, 1-propanol, 2-butanol, 2-methyl-propanol, ketones, like acetone, methylethylketone, methylisobutylketone, or an ester, like methyl acetate, ethyl acetate, butyl acetate, with at least a small amount of water present.
  • miscible solvents such as water
  • the pH of the solution is adjusted to about neutral, namely to pH 5.0-7.5 by adding an acid, as for instance acetic acid or ethylhexanoic acid.
  • an acid as for instance acetic acid or ethylhexanoic acid.
  • the way of dissolution will be known to those skilled in the art and will depend on the stability of the ⁇ -lactam compound in the solvent or in a mixture of solvents.
  • residence time and temperature should be as low as possible and a technique such as in-line mixing, for example a static mixer, can be attractive. If for example acetone is present, a residence time of several hours might be acceptable.
  • the ⁇ -lactam compound for example potassium clavulanate, present in the solvent dissolved or in suspension or in both forms, is contacted with a anti-solvent such as ketone, like acetone, methylethylketone, methylisobutylketone, or an ester, such as methyl acetate, ethyl acetate, butyl acetate or a mixture thereof, or an alcohol such as 1-propanol, 2-butanol, 2-methyl-propanol optionally containing a solvent for the ⁇ -lactam compound, such as water or an alcohol, like methanol or ethanol for potassium clavulanate.
  • a anti-solvent such as ketone, like acetone, methylethylketone, methylisobutylketone, or an ester, such as methyl acetate, ethyl acetate, butyl acetate or a mixture thereof, or an alcohol such as 1-propanol, 2-butan
  • the overall weight ratio of the solution containing the ß-lactam compound to the anti-solvent depends on the combination of solvents and on the desired agglomerate diameter, but generally lies within 0.05-10%. Also, it is possible to adjust this ratio by adding some solvent to the crystalliser before or during the process. This ratio will influence the average diameter of the agglomerates: the higher the relative volume of the solvent, the larger the agglomerates will be.
  • the solution of the ⁇ -lactam compound for instance a potassium clavulanate solution and the anti-solvent can be added simultaneously to the crystalliser or the solution of the ⁇ -lactam compound, for instance a potassium clavulanate solution can be added to the anti-solvent or the anti-solvent can be added to the solution of the ⁇ -lactam compound, for instance a potassium clavulanate solution.
  • the temperature should be kept below 50°C.
  • the use of seeding material can also be advantageous to enhance the agglomeration process.
  • the method of contacting the potassium clavulanate containing solution and the anti-solvent can be controlled via specific equipment, such as spray nozzles or capillaries. This contacting can occur in a vessel or in line or in a recycling loop over the vessel. It is also possible to first form droplets of solution of a certain diameter, after which the droplets are contacted with the anti-solvent.
  • Parameters such as the amount of nozzles, their diameter, the flow through the nozzles and the rotational speed of the mixer can be used to control the average particle size and density. In this way, several grades of agglomerates can be produced, with different physical properties.
  • the method of agitation is determined by the desired agglomeration size of the ⁇ -lactam compound.
  • the agitation should be moderate.
  • a common turbine agitator or pitched blade agitator can be used.
  • the general scales up parameters for agitation apply: the diameter of the blades versus the diameter of the vessel should be between 0.2-0.9, preferably between 0.2-0.5, depending on the type of agitator used.
  • the rotational speed (and thus shear), tip velocity, the size of the nozzle sprayer and power input determine the agglomerate size and density and can be used as control parameters.
  • high speed agitators such as toothed disks or rotor-stator mixers with multiple stage mixing/shearing action can be used. It is also possible to use in-line high shear mixers, with the advantage of short residence times. If needed, a recycle loop can be applied over such an in-line system. Another possibility is to combine a moderate shear mixer with a high shear mixer or a mill.
  • agglomerates with a diameter of the order of a magnitude of 1000 ⁇ m can be deagglomerated during the crystallisation using a high shear mixer, which is situated in the same crystalliser (such as mounted in the bottom) or as a separate unit after the crystalliser. Also, for example a colloid mill can be placed after the crystalliser for the same purpose.
  • the simultaneous crystallisation/agglomeration technique can be combined using ultrasonic crystallisation. This technique has been described for instance in Pharmaceutical Technology Europe, 9(9), 78 (1997 ). In this way different grades concerning particle size distribution, density, porosity and flowability can be easily achieved.
  • the residence time in the crystalliser and/or deagglomerator is determined by the desired average diameter of the agglomerates. For purposes of precipitation/crystallisation, long ageing times are not needed, as the crystals are formed immediately after contact with the anti-solvent. For agglomeration and deagglomeration, however, a certain minimum and maximum residence time will be valid, depending on parameters such as mixing time and volume of the vessel.
  • One of the embodiments of the invention is to have the excipients included in the agglomerates by addition of the same before, after or during the precipitation and/or agglomeration, such as cellulose, preferably microcrystalline cellulose, more preferably with a water activity ⁇ 0.2 at 25°C, most preferably Avicel® PH112.
  • cellulose preferably microcrystalline cellulose
  • a water activity ⁇ 0.2 at 25°C most preferably Avicel® PH112.
  • amorphous silica (Syloid® ) or colloidal silicon dioxide (Aerosil® ) can be used as excipient. All methods of mixing are possible: for example the excipient can be added before, simultaneously or after the addition of the ⁇ -lactam compound solution or - (partly) suspension to the crystalliser.
  • the excipients can be added as dry matter, suspended or dissolved in a solvent, preferably one of the solvents (or a mixture thereof) which is already used in the agglomeration process.
  • a solvent preferably one of the solvents (or a mixture thereof) which is already used in the agglomeration process.
  • Another embodiment of the present invention is that the crystallisation and agglomeration can occur in the presence of another active ß-lactam ingredient, for example amoxicillin trihydrate besides potassium clavulanate.
  • the amoxicillin can either be added as a solution or suspension leading to co-crystallisation, similar to the agglomeration in the presence of excipients.
  • the agglomerates of the present invention are not of the rosette type: they consist of small crystals clustered together in a random order (see the Figure).
  • the agglomerate size can easily be adjusted between about 1 and 1500 ⁇ m and also relatively small particles as with an average size of 100 ⁇ m or relatively large particles with an average size of 1000 ⁇ m may be prepared.
  • the amount of fines that either must be discharged of or that must be recycled, is small.
  • the agglomerates can easily be separated by for example, filtration or centrifugation and subsequently dried using conventional methods such as tumbling drying. It is also possible to include a classification process. For example, agglomerates of the desired size can be selectively removed from the crystalliser using gravity and/or a sieve. Fines or large particles which can be removed by sieving as well, can be recycled, either by addition in suspension or solution to the next batch.
  • pH-adjustment in order to adapt the pH of the end product can be achieved by adding an acid or base to the solution or the anti-solvent before contacting the streams of solvents containing the ⁇ -lactam compound and the anti-solvent. Also, acid or base can be added during the precipitation/crystallisation/ agglomeration process or even after the process.
  • potassium clavulanate agglomerates produced can have a loose bulk density between about 0.20 and 0.60 and a tapped bulk density between about 0.50 and 0.90 g/ml and a compressibility between about 10 and 40%.
  • the agglomerates prepared using the above method Due to the excellent flowability of the agglomerates prepared using the above method, they can be used for, for example, direct compression of tablets without the need for further pre-granulation. Moreover, due to the decreased surface area of the agglomerates, the degradation caused by chemical reactions on the surface (e.g. with water) may be reduced. The level of impurities in the agglomerates is also equal to or even lower than in case of conventional needles type crystals. As the bulk density increases significantly, large advantages can be achieved in the transportation as well as in the tabletting process: the final tablet volume can decrease significantly when using agglomerates compared to using needles.
  • the energy consumption of the present process is low, as the crystallisation process which is commonly present in the down stream process of pharmaceuticals can be combined with the agglomeration process.
  • the temperatures can be kept below 50°C during the complete agglomeration process, excipients-free agglomerates can be produced and handling of dry solids before the granulation does not occur, which is an important advantage in case of hygroscopic materials.
  • the solvents needed for the agglomeration can easily be recycled, possibly without the need for purification.
  • the possibility to make pure agglomerates of an unstable and hygroscopic product such as potassium clavulanate is highly attractive.
  • the agglomerates of the present invention can be used for all formulations to produce chew, swallow, disperse, effervescent or normal tablets of all sizes, forms and weights, also to fill hard gelatine capsules and to formulate dry syrups and for administering drugs with the help of a dose sipping device.
  • These agglomerates can also be used, for instance, in a pharmaceutical composition as a tablet of amoxicillin trihydrate produced from agglomerates of amoxicillin trihydrate and potassium clavulanate.
  • sterile agglomerates the solution of the ⁇ -lactam compounds, solvent and anti-solvent are sterilely filtered prior to crystallisation/agglomeration.
  • the solid material was filtered off and dried in vacuum at 30°C during 2-3 hours to give agglomerates of potassium clavulanate with an average diameter in the range of 100-1000 ⁇ m and a yield of 98% .
  • the content of the vessel was kept at about 1800 ml by periodically removing suspension through an outlet.Thereafter, the solid material was filtered off, washed with dry acetone and dried in vacuum at 30°C during 2-3 hours to yield potassium clavulanate agglomerates with an average diameter in the range of 500-1 500 ⁇ m.
  • Acetone (300 ml) and water (3 ml) were placed in a glass cylinder (100 mm in diameter, 150 mm height) equipped with a turbine stirrer (40 mm diameter), a two dropping funnel and a nitrogen inlet tube. Under stirring (900 rpm) simultaneously a solution of potassium clavulanate (30 g) in a water/acetone mixture (60 g, 1:1 w/w) and acetone (2000 ml) were added.
  • the contents of the vessel were kept at about 900 ml by removing a part of the contents with the help of an outlet.
  • the solid material was filtered off, washed with dry acetone and dried in vacuum at 30°C. Agglomerates of potassium clavulanate with an average particle diameter of 1000 ⁇ m were obtained in 98% yield.
  • Acetone (500 ml) and water (5 ml) were placed in an one litre 4-necked round-bottom flask equipped with a thermometer, Ultra-Turrax mixer (type T25 and shaft S25N-18G), two dropping funnels and a nitrogen inlet tube.
  • Example 5 The experiment was repeated as described in Example 5, but using a rotor-stator type high shear mixer (Silverson mixer with emulsion screen, i.e. a screen with spherical pores of about 1.5 mm) at 3000 rev/min.
  • a rotor-stator type high shear mixer Silicon mixer with emulsion screen, i.e. a screen with spherical pores of about 1.5 mm
  • Ethylacetate (400 ml) and water (1 ml) were placed in a glass cylinder (100 mm in diameter, 150 mm height) equipped with a turbine stirrer (40 mm diameter), a two dropping funnel and a nitrogen inlet tube. Under stirring (900 rpm) at the same time a solution of potassium clavulanate (10 g) in water (10 ml) and ethyl acetate (600 ml) were added.
  • the agglomerates of potassium clavulanate were prepared as described in Example 6, but using a Silverson mixer with general purpose disintegrating screen, i.e. a screen with square holes with a diameter of about 2.5 mm.
  • a thermometer and inlet for nitrogen acetone (1000 ml) and water (10 ml) were placed in a 2- litre flask equipped with the Silverson mixer.
  • a solution of potassium clavulanate (120 g) in a mixture of water/acetone (240 g, 1:1 w/w) and acetone (8000 ml) were added at 15-20°C.
  • the contents of the vessel was kept at about 1800 ml with an outlet.
  • the solid was filtered off, washed with acetone and dried in vacuum at 30°C during 2-3 hours to give agglomerates with an average diameter in the range of 40-200 ⁇ m.
  • Needles of potassium clavulanate were prepared by suspending diclavulanate salt of bis(2-dimethylaminoethyl) ether (100 g) in acetone (3350 ml) and water (50 ml). Under stirring a solution of potassium 2-ethylhexanoate (1450 ml, 0.34 M) in acetone at 5-10°C was added. After 1 hour stirring the mixture was filtered off, washed with dry acetone and dried in vacuum during 18 hours at room temperature to give 81.2 g of potassium clavulanate needles.
  • Table 1 Comparison of physical properties of potassium clavulanate in agglomerated and needle form, optionally mixed with Avicel PH112 in a ratio of 70 : 30 w/w% have been described in Table 1.
  • Table 1 Comparison of physical properties of potassium clavulanate in agglomerated and needle form, optionally mixed with Avicel PH112 Material Loose bulk density Tapped bulk density Compressibility Particle size distribution Agglomerates of potassium clavulanate 0.49g/ml 0.68g/ml 28% between 1 and 200 ⁇ m Needles of Potassium clavulanate 0.18g/ml 0.36g/ml 50% between 5 and 75 ⁇ m Agglomerates of potassium clavulanate mixed with Avicel PH112 0.43g/ml 0.61 g/ml 29% Not determined Needles of potassium clavulanate mixed with Avicel PH112 0.20g/ml 0.40g/ml 50% Not determined
  • agglomerated suspension was removed continuously from the crystalliser, centrifuged, washed with dry acetone and dried in vacuum at 30°C.
  • agglomerates such as shown on the Figure were produced with a loose bulk density of 0.22 g/ml, a tapped bulk density of 0.30 g/ml and a compressibility of 27%.
  • the particle size distribution is given in Table 2 and a photo made by an Electron-microscope of potassium clavulanate is shown in the Figure.
  • Table 2 Particle size distribution [volume %] ⁇ 75 ⁇ m 75-150 ⁇ m 150-250 ⁇ m 250-500 ⁇ m 500-710 ⁇ m > 710 ⁇ m 46.3 43.3 8 1 0.2 0.1
  • Table 3 Physical properties: particle size distribution [volume %] Loose bulk density [g/ml] Tapped bulk density [g/ml] Compressibility [%] ⁇ 75 ⁇ m 75-150 ⁇ m 150-250 ⁇ m 250-500 ⁇ m 500-710 ⁇ m > 710 ⁇ m 1000 RPM 0.39 0.44 11 5.1 6.5 20.7 60.8 6.1 0.2 2000 RPM 0.42 0.47 11 1.8 2.4 9.5 57.3 27 1.5
  • the solution flow was 15 l/h and the acetone flow was 312 l/h.
  • the flows were decreased by a factor 2.
  • the suspension was removed form the crystalliser using a pump.
  • the two agglomerated suspensions made were centrifuged, washed with dry acetone and dried in vacuum at 30°C.
  • the physical properties can be seen in Table 4.
  • Table 4 Physical properties: Particle size distribution [volume %] Loose bulk density [g/ml] Tapped bulk density [g/ml] Compressibility [%] ⁇ 75 ⁇ m 75-150 ⁇ m 150-250 ⁇ m 250-500 ⁇ m 500-710 ⁇ m > 710 ⁇ m High flow 0.27 0.36 25 48.7 41.2 9.3 0.3 0 0 Low flow 0.35 0.44 20 48.8 50.4 1.1 0.6 0.4 0
  • the rotational speed of the agitator was 3000 and the temperature was circa 15°C.
  • the suspension was removed from the crystalliser using a pump.
  • the two agglomerated suspensions made were centrifuged, washed with dry acetone and dried in vacuum at 30°C.
  • the physical properties can be seen in Table 5.
  • Table 5 Physical properties: particle size distribution [volume %] Nozzle diameter Loose bulk density [g/ml] Tapped bulk density [g/ml] Compressibility [%] ⁇ 75 ⁇ m 75-150 ⁇ m 150-250 ⁇ m 250-500 ⁇ m 500-710 ⁇ m > 710 ⁇ m 0.9 mm 0.22 0.3 0.27 46.3 43.3 8 1 0.2 0.1 1.2 mm 0.36 0.44 0.18 15.9 50.6 31.3 1.9 0 0.3

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)
  • Saccharide Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (23)

  1. Agglomérats sous forme cristalline comprenant un ou plusieurs composés bêta-lactames, dans lesquels au moins un composé bêta-lactame a une affinité élevée pour l'eau et contenant facultativement un ou plusieurs excipients, caractérisés en ce que les agglomérats ont une compressibilité entre environ 10-40 %, à condition que la forme cristalline de type rosette du clavulanate de potassium soit exclue et à condition que les agglomérats puissent être obtenus par un procédé dans lequel des agglomérats de taille moyenne des particules contrôlée sont produits dans une phase liquide en appliquant des dispositifs d'agitation et un pulvérisateur à buse.
  2. Agglomérats selon la revendication 1, dans lesquels les agglomérats sont substantiellement exempts de cristaux bêta-lactame non agglomérés.
  3. Agglomérats selon la revendication 1 ou 2, dans lesquels au moins un composé bêta-lactame est l'acide clavulanique.
  4. Agglomérats selon l'une quelconque des revendications 1-3 dans lesquels le composé bêta-lactame est le clavulanate de potassium.
  5. Agglomérats selon la revendication 4, constitués uniquement de clavulanate de potassium.
  6. Agglomérats selon la revendication 4 comprenant en outre de l'amoxicilline.
  7. Agglomérats selon l'une quelconque des revendications 1 à 4 ou 6, dans lesquels les excipients sont une microcellulose cristalline, de préférence Avicel®, ou une silice, de préférence Syloid® ou Aerosil®.
  8. Agglomérats selon l'une quelconque des revendications 1 à 7, où les agglomérats ont une taille moyenne des particules entre environ 1 µm et 1500 µm, de préférence entre environ 500 µm et 1500 µm, plus préférablement entre 800 µm et 1200 µm ou de préférence entre 1 µm et 300 µm, plus préférablement entre 1 µm et 200 µm.
  9. Agglomérats selon l'une quelconque des revendications 1 à 8 sous forme stérile.
  10. Procédé pour la préparation d'agglomérats cristallisés comprenant un ou plusieurs composés bêta-lactame, dans lequel au moins un composé bêta-lactame a une affinité élevée pour l'eau, dans lequel des agglomérats de taille moyenne des particules contrôlée sont produits dans une phase liquide par application de dispositifs d'agitation et d'un pulvérisateur à buse.
  11. Procédé selon la revendication 10, dans lequel la phase liquide comprend une solution ou une suspension d'au moins un composé bêta-lactame correspondant dans un solvant ou dans un mélange de solvants conjointement avec un ou plusieurs antisolvants.
  12. Procédé selon la revendication 11, dans lequel le rapport en poids de la solution contenant le composé bêta-lactame sur l'antisolvant va d'environ 0,05 à 10 % en poids.
  13. Procédé selon la revendication 11 ou 12, dans lequel le solvant est choisi parmi le groupe constitué d'eau, d'alcool, de cétone et d'ester ou d'un mélange de ceux-ci, l'eau étant présente.
  14. Procédé selon l'une quelconque des revendications 10 à 13, dans lequel l'antisolvant est une cétone, comme l'acétone, la méthyléthylcétone, ou un ester, comme l'acétate de méthyle, l'acétate d'éthyle, l'acétate d'isopropyle, l'acétate de butyle, ou un alcool comme le 1-propanol, le 1-butanol, le 2-butanol, le 2-méthyl-1-propanol ou un mélange de ces solvants, contenant facultativement de l'eau.
  15. Procédé selon l'une quelconque des revendications 10 à 14, dans lequel un ou plusieurs dispositifs d'agitation sont utilisés pour cristalliser, agglomérer et/ou désagglomérer le composé bêta-lactame et facultativement la classification et le mélange avec des excipients et/ou un autre composé bêta-lactame dans un traitement par lots ou en continu, dans une ou plusieurs unités.
  16. Procédé selon la revendication 15, dans lequel le procédé est effectué en appliquant des dispositifs d'agitation dans un ou plusieurs flacons, des mélangeurs en ligne ou une combinaison de ceux-ci.
  17. Procédé selon la revendication 15 ou 16, dans lequel un mélangeur à cisaillement élevé est utilisé comme dispositif d'agitation.
  18. Procédé selon l'une quelconque des revendications 10 à 17, caractérisé par la préparation d'agglomérats avec diverses tailles de particules, par l'utilisation subséquente d'une combinaison et permutation de différents dispositifs d'agitation et de leurs vitesses, du type et de la quantité des solvants utilisés et de la manière de mélanger un ou plusieurs solvants et antisolvants.
  19. Procédé selon l'une quelconque des revendications 10 à 18, caractérisé par la dissolution d'un ou plusieurs bêta-lactames correspondants dans un solvant, l'ajustement du pH à un pH environ neutre et le mélange avec l'antisolvant.
  20. Formulation pharmaceutique comprenant les agglomérats selon l'une quelconque des revendications 1 à 9 et un ou plusieurs excipients pharmaceutiquement acceptables.
  21. Formulation pharmaceutique comprenant de l'amoxicilline, de préférence de l'amoxicilline trihydratée et les agglomérats cristallins de clavulanate de potassium tels que définis dans la revendication 5, et facultativement un ou plusieurs excipients inertes pharmaceutiquement acceptables.
  22. Formulation pharmaceutique comprenant un mélange d'amoxicilline trihydratée et d'agglomérats cristallins de clavulanate de potassium et un ou plusieurs excipients inertes pharmaceutiquement acceptables comme défini dans la revendication 4.
  23. Forme dosée pharmaceutique comprenant une formulation pharmaceutique selon l'une quelconque des revendications 21 à 23.
EP00917035A 1999-04-01 2000-04-03 Agglomerats obtenus par cristallisation Expired - Lifetime EP1165049B2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
DE60008508T DE60008508T9 (de) 1999-04-01 2000-04-03 Agglomerate durch kristallisation
EP00917035A EP1165049B2 (fr) 1999-04-01 2000-04-03 Agglomerats obtenus par cristallisation
SI200030366T SI1165049T2 (sl) 1999-04-01 2000-04-03 Aglomerati s kristalizacijo

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99201034 1999-04-01
EP99201034 1999-04-01
PCT/EP2000/002917 WO2000041478A2 (fr) 1999-04-01 2000-04-03 Agglomerats obtenus par cristallisation
EP00917035A EP1165049B2 (fr) 1999-04-01 2000-04-03 Agglomerats obtenus par cristallisation

Publications (3)

Publication Number Publication Date
EP1165049A2 EP1165049A2 (fr) 2002-01-02
EP1165049B1 EP1165049B1 (fr) 2004-02-25
EP1165049B2 true EP1165049B2 (fr) 2011-07-06

Family

ID=8240058

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00917035A Expired - Lifetime EP1165049B2 (fr) 1999-04-01 2000-04-03 Agglomerats obtenus par cristallisation

Country Status (12)

Country Link
US (3) US6979735B1 (fr)
EP (1) EP1165049B2 (fr)
CN (1) CN1209099C (fr)
AT (1) ATE260096T1 (fr)
AU (1) AU3817300A (fr)
CA (1) CA2364342C (fr)
DE (1) DE60008508T9 (fr)
ES (1) ES2215628T5 (fr)
MX (1) MXPA01009808A (fr)
SI (1) SI1165049T2 (fr)
TR (1) TR200102771T2 (fr)
WO (1) WO2000041478A2 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
US7250176B1 (en) * 1999-04-13 2007-07-31 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
ATE286057T1 (de) * 2000-10-20 2005-01-15 Sandoz Ag Pharmazeutische zubereitungen enthaltend clavulansäure
GB0031267D0 (en) * 2000-12-21 2001-01-31 Smithkline Beecham Plc Novel compositions
EP1381362A2 (fr) * 2001-04-12 2004-01-21 Sandoz Gmbh Compositions pharmaceutiques
AT500131A1 (de) * 2002-02-01 2005-11-15 Sandoz Ag Organische verbindungen
AT500134A1 (de) * 2002-02-01 2005-11-15 Sandoz Ag Verfahren zur herstellung eines entmischungsstabilen granulats
AT500132A1 (de) * 2002-02-06 2005-11-15 Sandoz Ag Organische verbindungen
AT500133A1 (de) * 2002-02-06 2005-11-15 Sandoz Ag Verfahren zur herstellung eines entmischungsstabilen granulats
US7534781B2 (en) 2003-03-21 2009-05-19 Dsm Ip Assets B.V. Crystalline amoxicillin trihydrate powder
CN1761457B (zh) * 2003-03-21 2010-05-12 帝斯曼知识产权资产管理有限公司 三水羟氨苄青霉素
RS20050866A (en) * 2004-01-06 2007-08-03 Panacea Biotec Ltd., Controlled release pharmaceutical composition comprising an acid- insoluble and a bioadhesive polymer
EP3240563B1 (fr) 2014-12-29 2020-12-09 Bioventus LLC Systèmes et procédés pour l'apport amélioré de molécules ostéoinductrices dans la réparation osseuse
CN108905264A (zh) * 2018-07-17 2018-11-30 凯莱英医药集团（天津）股份有限公司 连续化结晶方法在β-内酰胺类抗生素合成中的应用及连续化结晶系统
US11905286B2 (en) 2018-08-09 2024-02-20 Antabio Sas Diazabicyclooctanones as inhibitors of serine beta-lactamases

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997033564A1 (fr) † 1996-03-13 1997-09-18 Biochemie Gesellschaft Mbh Agglomerats renfermant des composes de betalactamines
WO1998002145A2 (fr) † 1996-07-16 1998-01-22 Gist-Brocades B.V. GRANULES DE β-LACTAME SANS SOLVANTS ORGANIQUES
WO1998005305A1 (fr) † 1996-08-06 1998-02-12 Quadrant Holdings Cambridge Ltd. Forme posologique en comprime d'acide clavulanique et d'amoxicilline comportant un excipient a base de trehalose
US5869101A (en) † 1994-01-28 1999-02-09 Gebro Borschek Gesellschaft M.B.H. Process for the preparation of S(+)-ibuprofen-particles
WO1999011261A1 (fr) † 1997-08-29 1999-03-11 Dsm N.V. Granules exempts d'excipients

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3697506A (en) * 1970-08-07 1972-10-10 Pfizer Crystalline alkali metal salts of {60 -carboxybenzylpenicillin and process therefor
US3692781A (en) * 1971-02-26 1972-09-19 Glaxo Lab Ltd Recovery of pure cephalexin from acidic reaction mixtures
US4138555A (en) * 1971-05-14 1979-02-06 Glaxo Laboratories, Limited (6R,7R)-7-[2-aryl-2-(etherified oximino)acetamido]-3-carbamoyloxymethylceph-3-em-4-carboxylic acid 1-oxides
AR206201A1 (es) * 1972-06-29 1976-07-07 Ciba Geigy Ag Procedimiento para la obtencion de compuestos de acido 7beta-amino-3-cefem-3-01-4-carboxilico0-substituidos
US3932386A (en) * 1973-06-18 1976-01-13 American Home Products Corporation Sodium 6-(L-aminocyclohexane carboxamido)penicillanic acid
GB1563103A (en) * 1975-10-13 1980-03-19 Beecham Group Ltd Process for the preparation of clavulanic acid
NZ189022A (en) * 1977-12-08 1981-11-19 Beecham Group Ltd Pharmaceutically acceptable particles of clavulanates dispersed in a polymeric binder
US4454069A (en) * 1979-08-24 1984-06-12 Beecham Group Limited Clavulanic acid salts and their preparation from the tertiary butyl amine salt
EP0053893B1 (fr) * 1980-12-09 1985-03-20 Beecham Group Plc Dérivés de l'acide clavulanique, leur préparation et leur application
US4522701A (en) * 1982-02-11 1985-06-11 E. I. Du Pont De Nemours And Company Process for preparing an anisotropic aromatic pitch
US4456753A (en) 1983-02-07 1984-06-26 Pfizer Inc. Process for the manufacture of highly crystalline sodium cefoperazone
DE3314725A1 (de) * 1983-04-22 1984-10-25 Siemens AG, 1000 Berlin und 8000 München Oberflaechenwellen-resonatorfilter
US4659812A (en) * 1985-08-20 1987-04-21 Bristol-Myers Company Cephalosporin intermediates
GB8608962D0 (en) * 1986-04-12 1986-05-14 Beecham Group Plc Beta-lactam antibiotics
GR1000035B (el) 1987-01-29 1990-03-12 Beecham Group Plc Κλαβουλανικο καλιο.
US5288861A (en) * 1987-01-29 1994-02-22 Beecham Group Plc Potassium clavulanate in rosette form
WO1991000865A1 (fr) 1989-07-10 1991-01-24 Gema S.A. Nouvelle forme de cephradine stable, procede de production de celle-ci, et produits intermediaires utilises
GB9009473D0 (en) 1990-04-27 1990-06-20 Beecham Group Plc Pharmaceutical formulation
HU212573B (en) * 1991-02-12 1996-08-29 Pliva Pharm & Chem Works Process for producing 4-oxo-azetidine-2-sulfonic acids and their salts
GB9109862D0 (en) 1991-05-08 1991-07-03 Beecham Lab Sa Pharmaceutical formulations
AT400033B (de) * 1992-03-10 1995-09-25 Biochemie Gmbh Neues verfahren zur isolierung und reinigung von clavulansäure und zur herstellung von pharmakologisch verträglichen salzen derselben
SI9400107A (en) * 1994-03-02 1995-10-31 Lek Tovarna Farmacevtskih New process of the isolation of clavulanic acid and its pharmaceutical salts from fermented broth of streptomyces sp.p 6621 ferm p 2804.
GB9408117D0 (en) 1994-04-23 1994-06-15 Smithkline Beecham Corp Pharmaceutical formulations
DE4426973C1 (de) * 1994-07-29 1996-03-28 Degussa Verfahren zur Herstellung eines als Brennstoffzellenelektrode einsetzbaren Plattinlegierungskatalysators
US6414142B1 (en) 1996-06-13 2002-07-02 Smithkline Beecham Corporation Process for preparing potassium clavulanate
BR9713339A (pt) 1996-11-11 2000-05-09 Gist Brocades Bv Processo para preparação de sais e ésteres do ácido clavulânico.
ES2142641T3 (es) * 1997-03-24 2000-04-16 Cipan Comp Ind Prod Procedimiento para aislar una sal alcalino-metalica farmaceuticamente aceptable del acido clavulanico.

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5869101A (en) † 1994-01-28 1999-02-09 Gebro Borschek Gesellschaft M.B.H. Process for the preparation of S(+)-ibuprofen-particles
WO1997033564A1 (fr) † 1996-03-13 1997-09-18 Biochemie Gesellschaft Mbh Agglomerats renfermant des composes de betalactamines
WO1998002145A2 (fr) † 1996-07-16 1998-01-22 Gist-Brocades B.V. GRANULES DE β-LACTAME SANS SOLVANTS ORGANIQUES
WO1998005305A1 (fr) † 1996-08-06 1998-02-12 Quadrant Holdings Cambridge Ltd. Forme posologique en comprime d'acide clavulanique et d'amoxicilline comportant un excipient a base de trehalose
WO1999011261A1 (fr) † 1997-08-29 1999-03-11 Dsm N.V. Granules exempts d'excipients

Also Published As

Publication number Publication date
ES2215628T5 (es) 2011-11-28
WO2000041478A3 (fr) 2000-11-02
CA2364342C (fr) 2011-02-01
WO2000041478A2 (fr) 2000-07-20
ATE260096T1 (de) 2004-03-15
DE60008508T3 (de) 2012-01-19
ES2215628T3 (es) 2004-10-16
DE60008508T2 (de) 2004-12-23
EP1165049A2 (fr) 2002-01-02
DE60008508D1 (de) 2004-04-01
MXPA01009808A (es) 2002-04-24
US20110045082A1 (en) 2011-02-24
AU3817300A (en) 2000-08-01
SI1165049T2 (sl) 2011-11-30
SI1165049T1 (en) 2004-12-31
DE60008508T9 (de) 2012-06-14
US20060079496A1 (en) 2006-04-13
TR200102771T2 (tr) 2002-04-22
EP1165049B1 (fr) 2004-02-25
CA2364342A1 (fr) 2000-07-20
CN1345231A (zh) 2002-04-17
CN1209099C (zh) 2005-07-06
US6979735B1 (en) 2005-12-27

Similar Documents

Publication Publication Date Title
US20110045082A1 (en) Agglomerates by crystallisation
CN1089234C (zh) 微细颗粒的制造方法
US6558704B1 (en) Process for preparing pellets containing up to 90 wt.% of a pharmaceutical active ingredient
US20050003001A1 (en) Method for improving dissolution of poorly dispersible medicaments
CA2272402A1 (fr) Granules comprenant du clavulanate et un ou plusieurs excipients
US20090208999A1 (en) Crystalline amoxicillin trihydrate powder
SK96496A3 (en) Process for producing s(+)-ibuprofen particles
KR100926895B1 (ko) 측쇄 아미노산 함유 과립의 제조방법
CN1295472A (zh) 卡维地洛－盖仑制剂
CN114681404B (zh) 一种瑞格列奈颗粒剂药物组合物及其制备方法
CN1198595C (zh) 制备核黄素的喷雾颗粒的方法
US20060263424A1 (en) Pharmaceutical compositions comprising clavulanic acid
US6242006B1 (en) β-lactam granules free of organic solvents
CN1048396C (zh) 依布硒啉颗粒制剂
WO2003063820A2 (fr) Granulats stables a la segregation
JPH08231402A (ja) テオフィリン徐放性マイクロカプセルのドライシロップ剤およびその製造法
JP2004002245A (ja) 溶出性を改善したイトラコナゾール経口投与製剤
CN1774438A (zh) 以颗粒形式制备b/c型的核黄素的方法
AT500131A1 (de) Organische verbindungen
AT500134A1 (de) Verfahren zur herstellung eines entmischungsstabilen granulats

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010913

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI PAYMENT 20010913

17Q First examination report despatched

Effective date: 20021105

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: DSM IP ASSETS B.V.

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Extension state: SI

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040225

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60008508

Country of ref document: DE

Date of ref document: 20040401

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040403

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20040400967

Country of ref document: GR

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040430

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20040525

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20040225

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2215628

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PLBQ Unpublished change to opponent data

Free format text: ORIGINAL CODE: EPIDOS OPPO

PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

PLAX Notice of opposition and request to file observation + time limit sent

Free format text: ORIGINAL CODE: EPIDOSNOBS2

REG Reference to a national code

Ref country code: SI

Ref legal event code: IF

26 Opposition filed

Opponent name: SANDOZ AG

Effective date: 20041125

NLR1 Nl: opposition has been filed with the epo

Opponent name: SANDOZ AG

PLAX Notice of opposition and request to file observation + time limit sent

Free format text: ORIGINAL CODE: EPIDOSNOBS2

PLBB Reply of patent proprietor to notice(s) of opposition received

Free format text: ORIGINAL CODE: EPIDOSNOBS3

PLBP Opposition withdrawn

Free format text: ORIGINAL CODE: 0009264

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20040725

PLAY Examination report in opposition despatched + time limit

Free format text: ORIGINAL CODE: EPIDOSNORE2

PLAH Information related to despatch of examination report in opposition + time limit modified

Free format text: ORIGINAL CODE: EPIDOSCORE2

PLBC Reply to examination report in opposition received

Free format text: ORIGINAL CODE: EPIDOSNORE3

PUAH Patent maintained in amended form

Free format text: ORIGINAL CODE: 0009272

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: PATENT MAINTAINED AS AMENDED

27A Patent maintained in amended form

Effective date: 20110706

AK Designated contracting states

Kind code of ref document: B2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Extension state: SI

REG Reference to a national code

Ref country code: CH

Ref legal event code: AEN

Free format text: AUFRECHTERHALTUNG DES PATENTES IN GEAENDERTER FORM

REG Reference to a national code

Ref country code: DE

Ref legal event code: R102

Ref document number: 60008508

Country of ref document: DE

Effective date: 20110706

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: SE

Ref legal event code: RPEO

REG Reference to a national code

Ref country code: ES

Ref legal event code: DC2A

Ref document number: 2215628

Country of ref document: ES

Kind code of ref document: T5

Effective date: 20111128

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20110402328

Country of ref document: GR

Effective date: 20111117

REG Reference to a national code

Ref country code: NL

Ref legal event code: SD

Effective date: 20120403

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60008508

Country of ref document: DE

Representative=s name: DIEHL & PARTNER GBR, DE

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V.

Effective date: 20120605

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20120328

Year of fee payment: 13

Ref country code: GR

Payment date: 20120320

Year of fee payment: 13

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 60008508

Country of ref document: DE

Owner name: DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V., NL

Free format text: FORMER OWNER: DSM IP ASSETS B.V., HEERLEN, NL

Effective date: 20120515

Ref country code: DE

Ref legal event code: R082

Ref document number: 60008508

Country of ref document: DE

Representative=s name: DIEHL & PARTNER GBR, DE

Effective date: 20120515

Ref country code: DE

Ref legal event code: R082

Ref document number: 60008508

Country of ref document: DE

Representative=s name: PATENT- UND RECHTSANWAELTE DIEHL & PARTNER GBR, DE

Effective date: 20120515

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V.

Free format text: DSM IP ASSETS B.V.#HET OVERLOON 1#6411 TE HEERLEN (NL) -TRANSFER TO- DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V.#ALEXANDER FLEMINGLAAN 1#2613 AX DELFT (NL)

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20120413

Year of fee payment: 13

Ref country code: IE

Payment date: 20120411

Year of fee payment: 13

Ref country code: BE

Payment date: 20120412

Year of fee payment: 13

Ref country code: CH

Payment date: 20120412

Year of fee payment: 13

Ref country code: DE

Payment date: 20120419

Year of fee payment: 13

REG Reference to a national code

Ref country code: SI

Ref legal event code: SP73

Owner name: DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V.; NL

Effective date: 20120608

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20120504

Year of fee payment: 13

Ref country code: SE

Payment date: 20120411

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20120413

Year of fee payment: 13

Ref country code: CY

Payment date: 20120418

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20120510

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20120327

Year of fee payment: 13

REG Reference to a national code

Ref country code: AT

Ref legal event code: PC

Ref document number: 260096

Country of ref document: AT

Kind code of ref document: T

Owner name: DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V., NL

Effective date: 20130307

BERE Be: lapsed

Owner name: *DSM SINOCHEM PHARMACEUTICALS NETHERLANDS B.V.

Effective date: 20130430

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20131101

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 260096

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130430

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20130403

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20110402328

Country of ref document: GR

Effective date: 20131104

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130430

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131101

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130430

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130430

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130512

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130430

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130403

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130404

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20131231

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60008508

Country of ref document: DE

Effective date: 20131101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130430

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130403

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131104

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131101

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20140123

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130403

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130403

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20140606

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130404